We study the neurobiology of unipolar depression. Our goals are to understand fundamental pathophysiological mechanisms in this disorder, develop improved means for its diagnosis and treatment, and elucidate the mechanisms of its long-term somatic consequences. We utilize methods ranging from mathematical modeling of pulsatile hormonal secretion to molecular biology. Assessment of hypothalamic-pituitary-adrenal axis function (HPA) via every twenty-minute sampling over nine days revealed that all of our patients with atypical depression studied to date show qualitative (loss of complexity) and quantitative (decreased pulse burst mass and amplitude) abnormalities in HPA function, thus validating our hypothesis of pathological suppression of the stress system in a subgroup of depressed patients. We have developed a corticotropin releasing hormone antagonist that is orally active and that crosses the blood brain barrier, and have confirmed its safety, biological activity, and suitability for labeling (iodination) for SPECT studies. We showed that this antagonist blocks both the expression and development of conditioned fear in the rat and exerts long-term anxiolytic effects in non-human primates. Leptin signals nutritional status to the brain. We found that plasma leptin is secreted in a pulsatile fashion, and that its circadian rhythm is inverse to that of the HPA axis. Because leptin inhibits the HPA axis centrally, this finding implicates leptin in the tonic inhibition of the HPA axis and suggests that it may be a link between appetitive and HPA axis disturbances in depression. We also first showed that leptin secretion is synchronous with plasma LH and estradiol secretion in humans, indicating a physiologic and possibly pathophysiologic role for leptin in human reproduction. Our data show that 40% of premenopausal women with past or current depression show significant decrements in bone mineral density that render them susceptible to fracture. In the light of the 9-12% frequency of unipolar depression among women, this is a matter of significant public health concern.